ClinVar

The ClinVar variation report

The ClinVar variation report displays information from submitters aggregated by each variant (e.g. VCV123456789.1), rather than by the combination of variation-condition that is represented by the reference ClinVar accession (e.g. RCV123456789.1).  The variation display makes it easier to review what has been submitted per simple or complex allele, combining data that submitters may have provided with different disease names.

ClinVar defines a variation as the set of sequence changes about which an interpretation has been submitted. In other words, a "variation" may represent a single variant, a compound heterozygote, or a haplotype.

• The ClinVar variation report
• Title
• Interpretation
• Review status (stars)
• Submissions
• Last evaluated
• Accession
• Variation ID
• Description
• Variant details
• Conditions
• Genes
• Submitted interpretations and evidence
• Citations
• Dates
• Evidence details
• Feedback

Title

The title represents the preferred name of the variation (Figure 1A).

• For sequence variants within a gene, the name is constructed from the gene symbol and the HGVS expressions for the coding DNA and protein changes.
• For sequence variants that are larger than a gene, the name is the HGVS expression for the genomic DNA change.
• For structural variants, the name is constructed from the genome assembly name, cytogenetic location, genomic coordinates, and copy number, e.g.  GRCh38/hg38 1p31.1(chr1:71691191-72250907)x1

Figure 1.  The Title, Interpretation, and Variant details sections.

Interpretation

The top section reports the overall interpretation of a variation based on aggregating data from submitters (Figure 1B).  The details of what each submitter provided are listed in the Submitted interpretations and evidence section (Figure 4).

In the the variation report, the value reported for clinical significance for Mendelian disorders is based on a 3-level scale. Please see our detailed description of the representation of clinical significance in ClinVar and other variation resources at NCBI .

The values ClinVar and GTR use for clinical significance are maintained on GTR's ftp site.

https://ftp.ncbi.nlm.nih.gov/pub/GTR/standard_terms/Clinical_significance.txt

Review status (stars)

ClinVar reports the level of review supporting the assertion of clinical significance for the variation as review status. Stars provide a graphical representation of the review status on web pages. Please see our detailed description of the ClinVar review status.

Submissions

Count of submissions for the variant and the date of the most recent submission. Note: this is the total count, not the count of submissions providing an interpretation. Thus the total number of submissions may be higher than suggested by the review status.

Last evaluated

The most recent date that the variant was interpreted, or evaluated, by a submitter.

Accession

The VCV accession and version number. Read more about ClinVar's accession numbers.

Variation ID

The Variation ID is a unique identifier for the set of sequence changes that were interpreted. In other words, if the variation report is for a haplotype defined by five SNPs, there is a single Variation ID that represents that combination of SNPs in cis. Each individual SNP is represented by an Allele ID (see the Allele Description section).

Description

A brief description of the type of variant. - Short variants are described by the type of variant, e.g. single nucleotide variant or deletion. - CNVs are described by an estimate of the size and the type of variant, e.g. 597.8kb copy number gain. - Combinations of variants are described as either Haplotype or Genotype.

Variant details

The Variant details tab (Figure 1C) summarizes information about the variant, or set of variants, that was interpreted.

The Allele ID is an identifier for each individual nucleotide change in the set of variants that were interpreted. In other words, if the variation report is for interpretation of a haplotype defined by five SNPs, each SNP has its own Allele ID. The set of SNPs that make up the haplotype are represented by the Variation ID.

The Variant details tab reports names and HGVS representations, with links to other data sources about the variant itself.  The data in the Variant details section may come from submitters, but may also be added by NCBI, especially when the variant can be mapped to the genome.  Data usually provided by NCBI include:

• the type and length of the variant
• cytogenetic and genomic locations
• HGVS expressions:
  • on the current and previous chromosome sequence (NC accession)
  • on current NM/NPs and RefSeqGene (NG)
  • provided by submitters
• molecular consequence: a calculation of the effect of the sequence change, reported per transcript. ClinVar calculates the predicted molecular consequence, but does not predict functional consequence. Functional consequence (e.g. quantitative effects on gene expression, alternative splicing) is based on experimental evidence and must be submitted.
• the protein change, if applicable
• other names for the variant, e.g. deltaF508
• GMAF, the global minor allele frequency calculated by the 1000 Genomes Project
• allele frequency, with the source of the frequency data and the frequency of the stated allele
• links to related databases, such as dbSNP, dbVar, Variation Viewer, and LSDBs (locus-specific databases)

Conditions

The Conditions tab (Figure 2) provides a summary of condition-specific interpretations for the variant, including a link to the reference ClinVar record (RCV accession).

This tab also includes a summary of all clinical features that were observed in individuals with this variant and reported to ClinVar. More information about clinical features, including the submitter, are available on the Evidence details page.

Figure 2.  The Conditions tab.

Genes

The Genes tab (Figure 3) provides a summary of information about each gene affected by the variant. Most variants in ClinVar are short and are within a single gene so the Genes tab shows data for a single gene. CNVs may affect more than one gene; in this case, the genes tab displays the first ten genes, with preference given to genes that are curated on the ClinGen Dosage Sensitivity Map. If the CNV affects more than ten genes, there are links to NCBI's Variation Viewer, the UCSC browser, and the ClinGen Dosage Sensitivity Map to view all the genes.

The links for Related variants show you other variants from this gene in ClinVar. The link for "Within gene" shows you variants that affect only this gene, mostly short variants. The link for "All" shows you any variant that affects this gene, including both short variants and CNVs.

Figure 3.  The Genes tab.

Submitted interpretations and evidence

The Submitted interpretations and evidence section (Figure 4) provides a summary of data from the submitted records for the variant. The data in the columns are taken directly from the submitted record, i.e. these data are not aggregated by ClinVar.

Table 2. Columns in the Submitted interpretations and evidence table

Figure 4. The Submitted interpretations and evidence table

Citations

The Citations table lists publications about the variant. The vast majority of citations are provided by submitters; a small number have been curated by NCBI staff. Citations can be provided in several places in submissions; this table includes all citations except for those submitted on the condition and citations submitted as assertion criteria.

Dates

The date, "Record last updated", shown at the bottom of a VCV record represents the last date that the VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs) or to an update made by ClinVar, e.g. the addition of an HGVS expression or dbSNP rs number. This date may differ from the date of the "Most recent" submission reported at the top of the VCV record

Other dates reported on the page include:

• The date "First in ClinVar" in the Interpretation section represents the date when the VCV record first became public in ClinVar.
• The date "Last evaluated" in the Interpretation section represents the date the variant was most recently evaluated by a submitter.
• The date "Most recent" in the Interpretation section represents the date of the most recent submission (SCV) for the VCV record.
• The date "Last evaluated" in the section for Submitted interpretations and evidence represents the date the submitter last evaluated the variant.
• The date "First in ClinVar" in the section for Submitted interpretations and evidence represents the date when the submitted record (SCV) first became public in ClinVar.
• The date "Last updated" in the section for Submitted interpretations and evidence represents the date that the latest update to the submitted record (SCV) became public in ClinVar.

Evidence details

The Evidence details page displays many of the values displayed in the table for "Submitted interpretations and evidence", along with many more detailed data types. The data are presented as a table so that you can scan across multiple submissions for the same type of data.

A few columns are shown by default. Use the "Choose Columns" button at the lower left of the table to add more columns. Many of these data types are optional in submission so you may see empty columns. One approach is to add all columns to the display to see if data was submitted for any of the optional fields.

Feedback

We continue to make improvements to these pages. Please use the green Feedback button to let us know what improvements you'd like to see.